Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system

Detalhes bibliográficos
Autor(a) principal: Staudt, Keli Jaqueline
Data de Publicação: 2023
Outros Autores: Dias, Bruna Bernar, Alves, Izabel Almeida, Lelièvre, Bénédicte, Bouchara, Jean-Philippe, Araújo, Bibiana Verlindo de
Tipo de documento: Artigo
Idioma: eng
Título da fonte: Repositório Institucional da UFRGS
Texto Completo: http://hdl.handle.net/10183/281030
Resumo: Voriconazole is a triazole antifungal used empirically for the treatment of complicated meningitis associated with Cryptococcus neoformans. Biopsy studies show that the drug exhibits adequate brain penetration although levels of cerebral spinal fluid (CSF) are highly variable. Considering that CSF is one of the main surrogates for CNS exposure, the present work proposed the building of a population pharmacokinetic modeling (popPK) model able to describing the exposure achieved by voriconazole in the plasma, interstitial cerebral fluid and CSF of healthy and infected rats. The developed popPK model was described by four compartments, including total plasma, free brain and total CSF concentrations. The following PK parameters were determined: Km = 4.76 mg/L, Vmax = 1.06 mg/h, Q1 = 2.69 L, Qin = 0.81 h1 and Qout = 0.63 h1. Infection was a covariate in the Michaelis–Menten constant (Km) and intercompartmental clearance from the brain tissue compartment to central compartment (Qout). Simulations performed with the popPK model to determine the probability of reaching the therapeutic target of fAUC > MIC showed that VRC has sufficient tissue exposure in the interstitial fluid and in the CSF for the treatment of fungal infections in these tissues at prevalent minimum inhibitory concentrations.
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spelling Staudt, Keli JaquelineDias, Bruna BernarAlves, Izabel AlmeidaLelièvre, BénédicteBouchara, Jean-PhilippeAraújo, Bibiana Verlindo de2024-11-09T06:40:17Z20231999-4923http://hdl.handle.net/10183/281030001207256Voriconazole is a triazole antifungal used empirically for the treatment of complicated meningitis associated with Cryptococcus neoformans. Biopsy studies show that the drug exhibits adequate brain penetration although levels of cerebral spinal fluid (CSF) are highly variable. Considering that CSF is one of the main surrogates for CNS exposure, the present work proposed the building of a population pharmacokinetic modeling (popPK) model able to describing the exposure achieved by voriconazole in the plasma, interstitial cerebral fluid and CSF of healthy and infected rats. The developed popPK model was described by four compartments, including total plasma, free brain and total CSF concentrations. The following PK parameters were determined: Km = 4.76 mg/L, Vmax = 1.06 mg/h, Q1 = 2.69 L, Qin = 0.81 h1 and Qout = 0.63 h1. Infection was a covariate in the Michaelis–Menten constant (Km) and intercompartmental clearance from the brain tissue compartment to central compartment (Qout). Simulations performed with the popPK model to determine the probability of reaching the therapeutic target of fAUC > MIC showed that VRC has sufficient tissue exposure in the interstitial fluid and in the CSF for the treatment of fungal infections in these tissues at prevalent minimum inhibitory concentrations.application/pdfengPharmaceutics. Basel. Vol. 15, n. 7 (2023), 1781, 13 p.CriptococoseLíquido cefalorraquidianoVoriconazolMeningiteCryptococcosisCerebrospinal fluidVoriconazoleMeningitisBrain microdialysisInterstitial space fluidModeling and simulation as a tool to assess voriconazole exposure in the central nervous systemEstrangeiroinfo:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersioninfo:eu-repo/semantics/openAccessreponame:Repositório Institucional da UFRGSinstname:Universidade Federal do Rio Grande do Sul (UFRGS)instacron:UFRGSTEXT001207256.pdf.txt001207256.pdf.txtExtracted Texttext/plain46283http://www.lume.ufrgs.br/bitstream/10183/281030/2/001207256.pdf.txtb997140779f462130f81f73ed8a9be12MD52ORIGINAL001207256.pdfTexto completo (inglês)application/pdf2925075http://www.lume.ufrgs.br/bitstream/10183/281030/1/001207256.pdf81e558b5e5604d1f648733719a1c41bbMD5110183/2810302024-11-10 07:52:42.977124oai:www.lume.ufrgs.br:10183/281030Repositório InstitucionalPUBhttps://lume.ufrgs.br/oai/requestlume@ufrgs.bropendoar:2024-11-10T09:52:42Repositório Institucional da UFRGS - Universidade Federal do Rio Grande do Sul (UFRGS)false
dc.title.pt_BR.fl_str_mv Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system
title Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system
spellingShingle Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system
Staudt, Keli Jaqueline
Criptococose
Líquido cefalorraquidiano
Voriconazol
Meningite
Cryptococcosis
Cerebrospinal fluid
Voriconazole
Meningitis
Brain microdialysis
Interstitial space fluid
title_short Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system
title_full Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system
title_fullStr Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system
title_full_unstemmed Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system
title_sort Modeling and simulation as a tool to assess voriconazole exposure in the central nervous system
author Staudt, Keli Jaqueline
author_facet Staudt, Keli Jaqueline
Dias, Bruna Bernar
Alves, Izabel Almeida
Lelièvre, Bénédicte
Bouchara, Jean-Philippe
Araújo, Bibiana Verlindo de
author_role author
author2 Dias, Bruna Bernar
Alves, Izabel Almeida
Lelièvre, Bénédicte
Bouchara, Jean-Philippe
Araújo, Bibiana Verlindo de
author2_role author
author
author
author
author
dc.contributor.author.fl_str_mv Staudt, Keli Jaqueline
Dias, Bruna Bernar
Alves, Izabel Almeida
Lelièvre, Bénédicte
Bouchara, Jean-Philippe
Araújo, Bibiana Verlindo de
dc.subject.por.fl_str_mv Criptococose
Líquido cefalorraquidiano
Voriconazol
Meningite
topic Criptococose
Líquido cefalorraquidiano
Voriconazol
Meningite
Cryptococcosis
Cerebrospinal fluid
Voriconazole
Meningitis
Brain microdialysis
Interstitial space fluid
dc.subject.eng.fl_str_mv Cryptococcosis
Cerebrospinal fluid
Voriconazole
Meningitis
Brain microdialysis
Interstitial space fluid
description Voriconazole is a triazole antifungal used empirically for the treatment of complicated meningitis associated with Cryptococcus neoformans. Biopsy studies show that the drug exhibits adequate brain penetration although levels of cerebral spinal fluid (CSF) are highly variable. Considering that CSF is one of the main surrogates for CNS exposure, the present work proposed the building of a population pharmacokinetic modeling (popPK) model able to describing the exposure achieved by voriconazole in the plasma, interstitial cerebral fluid and CSF of healthy and infected rats. The developed popPK model was described by four compartments, including total plasma, free brain and total CSF concentrations. The following PK parameters were determined: Km = 4.76 mg/L, Vmax = 1.06 mg/h, Q1 = 2.69 L, Qin = 0.81 h1 and Qout = 0.63 h1. Infection was a covariate in the Michaelis–Menten constant (Km) and intercompartmental clearance from the brain tissue compartment to central compartment (Qout). Simulations performed with the popPK model to determine the probability of reaching the therapeutic target of fAUC > MIC showed that VRC has sufficient tissue exposure in the interstitial fluid and in the CSF for the treatment of fungal infections in these tissues at prevalent minimum inhibitory concentrations.
publishDate 2023
dc.date.issued.fl_str_mv 2023
dc.date.accessioned.fl_str_mv 2024-11-09T06:40:17Z
dc.type.driver.fl_str_mv Estrangeiro
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dc.identifier.uri.fl_str_mv http://hdl.handle.net/10183/281030
dc.identifier.issn.pt_BR.fl_str_mv 1999-4923
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url http://hdl.handle.net/10183/281030
dc.language.iso.fl_str_mv eng
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dc.relation.ispartof.pt_BR.fl_str_mv Pharmaceutics. Basel. Vol. 15, n. 7 (2023), 1781, 13 p.
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eu_rights_str_mv openAccess
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reponame_str Repositório Institucional da UFRGS
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